In the present study, the mechanisms of IgA B cell differentiation were further explored. It was established that IgA B cell differentiation requires several inter-related factors: 1) a B cell proliferative stimulus; 2) high concentrations of TGF-beta; 3) stimulation of B cells via the Ig receptor; and 4) Th2 cytokines IL-4/IL-5. A key fact is that TGF-beta, while necessary for initiation of IgA B cell differentiation, induces B cell apoptosis so that B cells in culture do not survive long enough to express IgA. This problem is overcome by co-stimulation with anti-IgD dextran, i.e., stimulation via the B cell Ig receptor which reverses TGF-beta-mediated apoptosis. In the Peyer?s patch high levels of TGF-beta are produced by specialized switch T cells, i.e., cells producing high levels of TGF- beta. These cells also interact with B cells via CD40L-CD40 molecules and provide signals necessary for high level IgA B cell differentiation provided B cells are protected from apoptosis by Ig receptor signaling. In vivo the latter is provided by follicular dendritic cells which presumably are highly charged with stimulatory antigens by virtue of their proximity to the mucosal lumen. - IgA, IgA B cell differentiation, TGF- beta, CD40L, IL-4, IL-5, B cell apoptosis.